There are currently only two platinum (Pt)-based drugs which are marketed and clinically used as antitumor drugs: cisplatin and carboplatin (FIG. 1). Common problems associated with these drugs include toxic side effects and low solubility in aqueous media. This invention provides method to synthesize novel Pt compounds with superior biological and physicochemical properties.
There are a large number of systems being pursued internationally, all of which are based on the modification of one and/or both of the ligand types coordinated to Pt. The principal design philosophy provided by this invention was to utilize active components in traditional Chinese medicine (TCM) with known therapeutic value, as the ligand choice (leaving group) for the synthesis of platinum based antitumor drugs.
Cantharidin is the active principle of "blister beetles" and has demonstrated high affinity and specificity towards the liver. In TCM, cantharidin is mainly used for treatment of liver, lung, intestinal and digestive tract tumors. However, severe side effects due to cantharidin has been documented, including nausea and vomiting, dysphagia, hematemesis, gross hematuria and dysuria.
Demethyl cantharidin (FIG. 1) was selected as a ligand for the synthesis of a novel series of Pt complexes because:
1. It is structurally similar to cantharidin, therefore should present similar structure-activity relationship (SAR). The novel Pt complexes may be specifically targeted towards liver and gastrointestinal tract tumors. PA1 2. It has lower toxicity (LD.sub.50 4 mg/kg) than cantharidin (LD.sub.50 1 mg/kg) and its corresponding dicarboxylic acid is also less toxic (LD.sub.50 14 mg/kg). PA1 3. The structures of the compounds provided by this disclosure resemble that of carboplatin, an established second generation platinum antitumor drug currently in clinical use as an effective antitumor agent.